Details of the Drug Combination

General Information of Drug Combination (ID: DCR8D4X)

• Drug Combination Name: Trientine Hydrochloride + Penicillamine
• Indication: Wilson Disease; Status: Phase 3 [1]
• Component Drugs:
  Trientine Hydrochloride (DM0KCV1): Small molecular drug
  Penicillamine (DM40EF6): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Trientine Hydrochloride

Disease Entry	ICD 11	Status	REF
Wilson disease	5C64.00	Approved	[2]

Indication(s) of Penicillamine

Disease Entry	ICD 11	Status	REF
Cystinuria	5C60.2	Approved	[3]
Rheumatoid arthritis	FA20	Approved	[4]
Wilson disease	5C64.00	Investigative	[3]

Penicillamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Tat protein (HIV tat)	TTT3ZC9	TAT_HV1H2	Inhibitor	[6]

Penicillamine Interacts with 47 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Elastin (ELN)	OTFSO7PG	ELN_HUMAN	Affects Localization	[7]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases ADR	[8]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Decreases Activity	[9]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[10]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[10]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[10]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Expression	[10]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[10]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[10]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[10]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[10]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[10]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[10]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[10]
Heat shock 70 kDa protein 6 (HSPA6)	OTH4S7WB	HSP76_HUMAN	Increases Expression	[10]
Early growth response protein 1 (EGR1)	OTCP6XGZ	EGR1_HUMAN	Increases Expression	[10]
Glutathione S-transferase Mu 3 (GSTM3)	OTLA2WJT	GSTM3_HUMAN	Increases Expression	[10]
Prostaglandin G/H synthase 1 (PTGS1)	OTHCRLEC	PGH1_HUMAN	Increases Expression	[10]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[10]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Increases Expression	[10]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Increases Expression	[10]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[10]
Flavin-containing monooxygenase 5 (FMO5)	OTTILF8T	FMO5_HUMAN	Increases Expression	[10]
Heat shock-related 70 kDa protein 2 (HSPA2)	OTSDET7B	HSP72_HUMAN	Increases Expression	[10]
Flavin-containing monooxygenase 1 (FMO1)	OTTHSQKP	FMO1_HUMAN	Increases Expression	[10]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[10]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[10]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Decreases Expression	[10]
High affinity copper uptake protein 1 (SLC31A1)	OTXLRTUB	COPT1_HUMAN	Increases Expression	[11]
Haptoglobin (HP)	OTGUGAF9	HPT_HUMAN	Decreases Expression	[12]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[13]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[12]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Metabolism	[14]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Decreases Secretion	[15]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Increases Expression	[11]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[5]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Decreases Expression	[16]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[17]
Lysyl oxidase homolog 2 (LOXL2)	OTRT46B5	LOXL2_HUMAN	Decreases Activity	[18]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Response To Substance	[19]
MHC class I antigen (HLA-B)	OTGPIQEH	O19755_HUMAN	Increases ADR	[8]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Response To Substance	[20]
MHC class I antigen HLA-B18 (HLA-B18)	OTO1T7OA	O77967_HUMAN	Increases ADR	[8]
HLA-DR4 protein (HLA-DR4)	OTR8MHXB	O77963_HUMAN	Increases ADR	[8]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Increases Response To Substance	[21]
HLA-DR3 (HLA-DRB1)	OTZ84GNP	Q29887_HUMAN	Increases ADR	[8]

References

• [1] ClinicalTrials.gov (NCT03539952) Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Penicillamine FDA Label
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7264).
• [5] N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway. Mol Carcinog. 2010 Jan;49(1):68-74. doi: 10.1002/mc.20578.
• [6] Docking studies reveal a selective binding of D-penicillamine to the transactivator protein of human immunodeficiency virus type 1. FEBS Lett. 2002 Apr 10;516(1-3):43-6.
• [7] Collagen and elastin changes in D-penicillamine-induced pseudoxanthoma elasticum-like skin. Br J Dermatol. 1986 Mar;114(3):381-8. doi: 10.1111/j.1365-2133.1986.tb02832.x.
• [8] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [9] Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms. Microvasc Res. 2009 May;77(3):314-26.
• [10] D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. Apoptosis. 2012 Oct;17(10):1079-94.
• [11] Mechanistic basis for overcoming platinum resistance using copper chelating agents. Mol Cancer Ther. 2012 Nov;11(11):2483-94. doi: 10.1158/1535-7163.MCT-12-0580. Epub 2012 Aug 21.
• [12] The influence of alclofenac treatment on acute-phase proteins, plasma tryptophan, and erythrocyte sedimentation rate in patients with rheumatoid arthritis. Curr Med Res Opin. 1975;3(5):286-97. doi: 10.1185/03007997509114779.
• [13] Massive breast enlargement in a patient receiving D-penicillamine for systemic sclerosis. J Rheumatol. 1985 Oct;12(5):990-1.
• [14] Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease. J Struct Biol. 2000 Jun;130(2-3):209-16. doi: 10.1006/jsbi.2000.4285.
• [15] Effect of anti-rheumatic drugs on the release of lysosomal enzymes from human leukocytes. Z Rheumatol. 1984 Jan-Feb;43(1):23-6.
• [16] The effect of zinc and D-penicillamine in a stable human hepatoma ATP7B knockout cell line. PLoS One. 2014 Jun 3;9(6):e98809. doi: 10.1371/journal.pone.0098809. eCollection 2014.
• [17] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [18] Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 2005 Sep;43(3):499-507. doi: 10.1016/j.jhep.2005.02.052.
• [19] Genetic markers in rheumatoid arthritis relationship to toxicity from D-penicillamine. J Rheumatol. 1986 Apr;13(2):269-73.
• [20] Longterm followup of treatment with D-penicillamine for rheumatoid arthritis: effectivity and toxicity in relation to HLA antigens. J Rheumatol. 1987 Dec;14(6):1115-9.
• [21] HLA-DR antigens and proteinuria induced by aurothioglucose and D-penicillamine in patients with rheumatoid arthritis. J Rheumatol. 1983 Dec;10(6):948-53.